Abstract
Development of severe disease in Plasmodium falciparum malaria infection is thought to be, at least in part, due to the sequestration of trophozoite-stage infected red blood cells in the microvasculature. The process of cytoadherence is mediated by binding of the parasite protein PfEMP-1 on the surface of infected red blood cells to endothelial cell receptors. Although antimalarial treatments rapidly kill parasites, significant mortality is still seen in severe malaria, particularly within 24h of hospital admission. We find that cytoadherence of infected red blood cells continues for several hours after killing of the parasite by antimalarials; after 24h treatment using a range of antimalarials binding is approximately one-third the level of untreated parasite cultures. This is consistent with the maintained presence of PfEMP-1 on the surface of drug-treated infected red blood cells. A specific advantage of artesunate over other treatments tested is seen on addition of this drug to younger ring stage parasites, which do not mature to the cytoadherent trophozoite-stage. These findings show that cytoadherence, a potential pathogenic property of P. falciparum infected red blood cells, continues long after the parasite has been killed. These data support the development of adjunctive therapies to reverse the pathophysiological consequences of cytoadherence.
Highlights
Plasmodium falciparum malaria is responsible for over a million deaths a year [1] with many of these fatalities occurring in infants in Africa
Using a range of antimalarials we show that non-viable P. falciparum infected red blood cells (iRBCs) retain the ability to cytoadhere at least 24 h after drug administration as a result of the slow rate of degradation of the surface protein Plasmodium falciparum erythrocyte membrane protein 1 (PfEMP-1)
Cytoadherence of iRBC occurs during the second part of the 48 h intraerythrocytic cycle of the parasite, and no significant changes in the level of cytoadherence of untreated, developing iRBC occur after adhesion reaches a maximum at 24–26 h post-invasion
Summary
Plasmodium falciparum malaria is responsible for over a million deaths a year [1] with many of these fatalities occurring in infants in Africa. An important aspect of the pathogenesis of severe malaria results from the ability of infected red blood cells to sequester in the microvasculature. During the 48 h parasite growth stage inside a host red blood cell the parasite makes many changes to the cell. As well as becoming more metabolically active, and more rigid, the infected red blood cell becomes capable of adhering to the endothelial cells lining the blood vessels [2]. Post-mortem studies of severe malaria show high levels of infected red blood cells (iRBCs) bound to microvasculature [3,4]. The involvement of sequestration in pathogenesis could be directly a result of blocking of the blood vessels, and/or downstream effects caused by the interaction
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